FOXO1-KLF10 reinforcing loop promotes adipose lipolysis to facilitate exercise-induced anti-obesity effect in male mice

Exercise is recognized to be an effective way in the combat against obesity and related metabolic disorders, but the underlying mechanism is incompletely understood. Krüppel-like factor 10 (KLF10) is a transcription factor participating in diverse biological processes. KLF10 expression is abundant in adipose tissue, but its role in obesity is not well defined. Here, we show that exercise could facilitate adipocyte-derived KLF10 expression via the SIRT1/FOXO1 pathway. Adipocyte-specific knockout of KLF10 (KLF10AKO) blunts exercise-promoted white adipose browning, energy expenditure, fat loss, and glucose tolerance in diet-induced obese (DIO) mice. On the contrary, adipocyte-specific transgenic expression of KLF10 in mice (KLF10ATG) enhanced the abovementioned metabolic benefits induced by exercise. Mechanistically, KLF10 interacts with FOXO1 and facilitates the recruitment of KDM4A to form a ternary complex on the promoter regions of the Pnpla2 and Lipe genes to promote the expression of these key lipolytic genes, therefore facilitating lipolysis to defend against DIO in mice. As a newfound downstream effector responding to exercise, adipose KLF10 could act as a potential target in the fight against obesity To gain the mechanistic insight into the role of KLF10 in adipose metabolism, RNA sequencing (RNA-seq) was conducted to investigate the differentially expressed genes (DEGs) in iWAT collected from HFD-fed WT and KLF10AKO mice.